1. Field of the Invention:
The present invention relates to methods and compositions for treating inflammatory diseases.
2. Discussion of the Background:
The release of inflammatory cytokines such as tumor necrosis factor-alpha (TNF.alpha.) by leukocytes is a means by which the immune system combats pathogenic invasions, including infections. Cytokines stimulate neutrophils to enhance oxidative (e.g. superoxide and secondary products) and nonoxidative (e.g. myeloperoxidase and other enzymes) inflammatory activity. Inappropriate and over-release of cytokines can produce counterproductive exaggerated pathogenic effects through the release of tissue damaging oxidative and nonoxidative products (Tracey, K. G., et al, J. Exp. Med., vol. 167, pp. 1211-1227 (1988); and Mannel, D. N., et al, Rev. Infect. Dis., vol. 9 (suppl 5), pp. S602-S606 (1987)).
For example, inflammatory cytokines have been shown to be pathogenic in: arthritis (Dinarello, C. A., Semin. Immunol., vol. 4, pp. 133-45 (1992)); ischemia (Seekamp, A., et al, Agents-Actions-Suppl., vol. 41, pp. 137-52 (1993)); septic shock (Mannel, D. N., et al, Rev. Infect. Dis., vol. 9, (suppl 5), pp. S602-S606 (1987)); asthma (Cembrzynska Nowak M., et al, Am. Rev. Respir. Dis., vol. 147, pp. 291-5 (1993)); organ transplant rejection (Imagawa, D. K., et al, Transplantation, vol. 51, pp. 57-62 (1991)); multiple sclerosis (Hartung, H.-P., Ann. Neurol., vol. 33, pp. 591-6 (1993)); and AIDS (Matsuyama, T., et al, AIDS, vol. 5, pp. 1405-1417 (1991)). In addition, superoxide formation in leukocytes has been implicated in promoting replication of the human immunodeficiency virus (HIV) (Legrand-Poels, S., et al, AIDS Res. Hum. Retroviruses, vol. 6, pp. 1389-1397 (1990)).
It is well known that adenosine and some relatively non-specific analogs of adenosine decrease neutrophil production of inflammatory oxidative products (Cronstein, B. N., et al, Ann. N.Y. Acad. Sci., vol. 451, pp. 291-314 (1985); Roberts, P. A., et al, Biochem. J., vol.227, pp. 669-674 (1985); Schrier, D. J., et al, J. Immunol., vol. 137, pp. 3284-3289 (1986); Cronstein, B. N., et al, Clinical Immunol. and Immunopath., vol. 42, pp. 76-85 (1987); lannone, M. A., et al, in Topics and Perspectives in Adenosine Research, E. Gerlach et al, eds., Springer-Verlag, Berlin, pp. 286-298 (1987); McGarrity, S. T., et al, J. Leukocyte Biol., vol. 44, pp. 411-421 (1988); De La Harpe, J., et al, J. Immunol., vol. 143, pp. 596-602 (1989); McGarrity, S. T., et al, J. Immunol., vol. 142, pp. 1986-1994 (1989); and Nielson, C. P., et al, Br. J. Pharmacol., vol. 97, pp. 882-888 (1989)). For example, adenosine has been shown to inhibit superoxide release from neutrophils stimulated by chemoattractants such as the synthetic mimic of bacterial peptides, f-met-leu-phe (fMLP), and the complement component C.sub.5 a (Cronstein, B. N., et al, J. Immunol., vol. 135, pp. 1366-1371 (1985)). Adenosine can decrease the greatly enhanced oxidative burst of PMN first primed with TNF.alpha. and then stimulated by a second stimulus such as f-met-leu-phe (Sullivan, G. W., et al, Clin. Res., vol. 41, p. 172A (1993)). There is evidence that in vivo adenosine has anti-inflammatory activity (Firestein, G. S., et al, Clin. Res., vol. 41, p. 170A (1993); and Cronstein, B. N., et al, Clin. Res., vol. 41, p. 244A (1993)).
It has been suggested that there is more than one subtype of adenosine receptor on neutrophils that have opposite effects on superoxide release (Cronstein, B. N., et al, J. Clin. Invest., vol. 85, pp. 1150-1157 (1990)). The existence of A.sub.2a receptor on neutrophils was originally demonstrated by Van Calker et al (Van Calker, D., et al, Eur. J. Pharmacology, vol. 206, pp. 285-290 (1991)).
There has been progressive development of compounds that are more and more potent and selective as agonists of A.sub.2a adenosine receptors based on radioligand binding assays and physiological responses. Initially, compounds with little or no selectivity for A.sub.2a receptors were used, such as adenosine itself or 5'-carboxamides of adenosine, such as 5'-N-ethylcarboxamidoadenosine (NECA) (Cronstein, B. N., et al, J. Immunol., vol. 135, pp. 1366-1371 (1985)). Later, it was shown that addition of 2-alkylamino substituents increased potency and selectivity, e.g. CV1808 and CGS21680 (Jarvis, M. F., et al, J. Pharmacol. Exp. Ther., vol. 251, pp. 888-893 (1989)). Additionally, it has been reported that adenosine can decrease the rate of HIV replication in a T-cell line (Sipka, S., et al, Acta. Biochim. Biopys. Hung., vol. 23, pp. 75-82 (1988)). 2-Alkoxy-substituted adenosine derivatives such as WRC0090 are even more potent and selective as agonists on the coronary artery A.sub.2a receptor (Ukena, M., et al, J. Med. Chem., vol. 34, pp. 1334-1339 (1991)). The 2-alkylhydrazino adenosine derivatives, e.g. SHA 211 (also called WRC-0470) have also been evaluated as agonists at the coronary artery A.sub.2a receptor (Niiya, K., et al, J. Med. Chem., vol. 35, pp. 4557-4561 (1992)).
There is one report of the combination of relatively non-specific adenosine analogs, D-phenylisopropyladenosine (D-PIA) and 2-chloroadenosine (Cl-Ado) with a phosphodiesterase inhibitor resulting in a lowering of neutrophil oxidative activity (Iannone, M. A., et al, in Topics and Perspectives in Adenosine Research, E. Gerlach et al, Eds., Springer-Verlag, Berlin, pp. 286-298 (1987)). However, such non-specific analogs are actually more potent activators of A.sub.1 adenosine receptors than of A.sub.2a adenosine receptors and, thus, are likely to cause side effects due to activation of A.sub.1 receptors on other tissues causing effects such as "heart block".
Thus, there remains a need for a method for treating inflammation. There also remains a need for pharmaceutical compositions useful for treating inflammation.